Dysbiosis Contributes to Arthritis Development via Activation of Autoreactive T Cells in the Intestine

Yuichi Maeda, Takashi Kurakawa, Eiji Umemoto, Daisuke Motooka, Yoshinaga Ito, Kazuyoshi Goto, Keiji Hirota, Masato Matsushita, Yoki Furuta, Masashi Narazaki, Noriko Sakaguchi, Hisako Kayama, Shota Nakamura, Tetsuya Iida, Yukihiko Saeki, Atsushi Kumanogoh, Shimon Sakaguchi, Kiyoshi Takeda

Research output: Contribution to journalArticle

129 Citations (Scopus)

Abstract

Objective: The intestinal microbiota is involved in the pathogenesis of arthritis. Altered microbiota composition has been demonstrated in patients with rheumatoid arthritis (RA). However, it remains unclear how dysbiosis contributes to the development of arthritis. The aim of this study was to investigate whether altered composition of human intestinal microbiota in RA patients contributes to the development of arthritis. Methods: We analyzed the fecal microbiota of patients with early RA and healthy controls, using 16S ribosomal RNA−based deep sequencing. We inoculated fecal samples from RA patients and healthy controls into germ-free arthritis-prone SKG mice and evaluated the immune responses. We also analyzed whether the lymphocytes of SKG mice harboring microbiota from RA patients react with the arthritis-related autoantigen 60S ribosomal protein L23a (RPL23A). Results: A subpopulation of patients with early RA harbored intestinal microbiota dominated by Prevotella copri; SKG mice harboring microbiota from RA patients had an increased number of intestinal Th17 cells and developed severe arthritis when treated with zymosan. Lymphocytes in regional lymph nodes and the colon, but not the spleen, of these mice showed enhanced interleukin-17 (IL-17) responses to RPL23A. Naive SKG mouse T cells cocultured with P copri−stimulated dendritic cells produced IL-17 in response to RPL23A and rapidly induced arthritis. Conclusion: We demonstrated that dysbiosis increases sensitivity to arthritis via activation of autoreactive T cells in the intestine. Autoreactive SKG mouse T cells are activated by dysbiotic microbiota in the intestine, causing joint inflammation. Dysbiosis is an environmental factor that triggers arthritis development in genetically susceptible mice.

Original languageEnglish
Pages (from-to)2646-2661
Number of pages16
JournalArthritis and Rheumatology
Volume68
Issue number11
DOIs
Publication statusPublished - Nov 1 2016

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Dysbiosis
Arthritis
Intestines
T-Lymphocytes
Rheumatoid Arthritis
Microbiota
Ribosomal Proteins
Interleukin-17
Prevotella
Lymphocytes
Th17 Cells
High-Throughput Nucleotide Sequencing
Zymosan
Autoantigens
Dendritic Cells
Colon
Spleen
Joints
Lymph Nodes
Inflammation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology

Cite this

Dysbiosis Contributes to Arthritis Development via Activation of Autoreactive T Cells in the Intestine. / Maeda, Yuichi; Kurakawa, Takashi; Umemoto, Eiji; Motooka, Daisuke; Ito, Yoshinaga; Goto, Kazuyoshi; Hirota, Keiji; Matsushita, Masato; Furuta, Yoki; Narazaki, Masashi; Sakaguchi, Noriko; Kayama, Hisako; Nakamura, Shota; Iida, Tetsuya; Saeki, Yukihiko; Kumanogoh, Atsushi; Sakaguchi, Shimon; Takeda, Kiyoshi.

In: Arthritis and Rheumatology, Vol. 68, No. 11, 01.11.2016, p. 2646-2661.

Research output: Contribution to journalArticle

Maeda, Y, Kurakawa, T, Umemoto, E, Motooka, D, Ito, Y, Goto, K, Hirota, K, Matsushita, M, Furuta, Y, Narazaki, M, Sakaguchi, N, Kayama, H, Nakamura, S, Iida, T, Saeki, Y, Kumanogoh, A, Sakaguchi, S & Takeda, K 2016, 'Dysbiosis Contributes to Arthritis Development via Activation of Autoreactive T Cells in the Intestine', Arthritis and Rheumatology, vol. 68, no. 11, pp. 2646-2661. https://doi.org/10.1002/art.39783
Maeda, Yuichi ; Kurakawa, Takashi ; Umemoto, Eiji ; Motooka, Daisuke ; Ito, Yoshinaga ; Goto, Kazuyoshi ; Hirota, Keiji ; Matsushita, Masato ; Furuta, Yoki ; Narazaki, Masashi ; Sakaguchi, Noriko ; Kayama, Hisako ; Nakamura, Shota ; Iida, Tetsuya ; Saeki, Yukihiko ; Kumanogoh, Atsushi ; Sakaguchi, Shimon ; Takeda, Kiyoshi. / Dysbiosis Contributes to Arthritis Development via Activation of Autoreactive T Cells in the Intestine. In: Arthritis and Rheumatology. 2016 ; Vol. 68, No. 11. pp. 2646-2661.
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AU - Ito, Yoshinaga

AU - Goto, Kazuyoshi

AU - Hirota, Keiji

AU - Matsushita, Masato

AU - Furuta, Yoki

AU - Narazaki, Masashi

AU - Sakaguchi, Noriko

AU - Kayama, Hisako

AU - Nakamura, Shota

AU - Iida, Tetsuya

AU - Saeki, Yukihiko

AU - Kumanogoh, Atsushi

AU - Sakaguchi, Shimon

AU - Takeda, Kiyoshi

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N2 - Objective: The intestinal microbiota is involved in the pathogenesis of arthritis. Altered microbiota composition has been demonstrated in patients with rheumatoid arthritis (RA). However, it remains unclear how dysbiosis contributes to the development of arthritis. The aim of this study was to investigate whether altered composition of human intestinal microbiota in RA patients contributes to the development of arthritis. Methods: We analyzed the fecal microbiota of patients with early RA and healthy controls, using 16S ribosomal RNA−based deep sequencing. We inoculated fecal samples from RA patients and healthy controls into germ-free arthritis-prone SKG mice and evaluated the immune responses. We also analyzed whether the lymphocytes of SKG mice harboring microbiota from RA patients react with the arthritis-related autoantigen 60S ribosomal protein L23a (RPL23A). Results: A subpopulation of patients with early RA harbored intestinal microbiota dominated by Prevotella copri; SKG mice harboring microbiota from RA patients had an increased number of intestinal Th17 cells and developed severe arthritis when treated with zymosan. Lymphocytes in regional lymph nodes and the colon, but not the spleen, of these mice showed enhanced interleukin-17 (IL-17) responses to RPL23A. Naive SKG mouse T cells cocultured with P copri−stimulated dendritic cells produced IL-17 in response to RPL23A and rapidly induced arthritis. Conclusion: We demonstrated that dysbiosis increases sensitivity to arthritis via activation of autoreactive T cells in the intestine. Autoreactive SKG mouse T cells are activated by dysbiotic microbiota in the intestine, causing joint inflammation. Dysbiosis is an environmental factor that triggers arthritis development in genetically susceptible mice.

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